Method of preparation of azaindole derivatives

ABSTRACT

A method of preparing azaindole compounds for antiviral use having the formula

CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims the benefit of U.S. Provisional Application Ser.No. 60/705,230 filed Aug. 3, 2005.

FIELD OF THE INNENTION

The present invention provides a method of preparing an azaindolederivative. The azaindole derivative demonstrates antiviral activity fortreatment of HIV and AIDS.

BACKGROUND OF THE RELATED TECHNOLOGY

HIV-1 (human immunodeficiency virus-1) infection remains a major medicalproblem, with an estimated 33.6 million people infected worldwide. Thenumber of cases of HIV and AIDS (acquired immunodeficiency syndrome) hasrisen rapidly. In 1999, 5.6 million new infections were reported, and2.6 million people died from AIDS. Currently available drugs for thetreatment of HIV include six nucleoside reverse transcriptase (RT)inhibitors (zidovudine, didanosine, stavudine, lamivudine, zalcitabineand abacavir), three non-nucleoside reverse transcriptase inhibitors(nevirapine, delavirdine and efavirenz), and five peptidomimeticprotease inhibitors (saquinavir, indinavir, ritonavir, nelfmavir andamprenavir). Each of these drugs can only transiently restrain viralreplication if used alone. However, when used in combination, thesedrugs have a profound effect on viremia and disease progression. Infact, significant reductions in death rates among AIDS patients havebeen recently documented as a consequence of the widespread applicationof combination therapy. However, despite these impressive results, 30 to50% of patients ultimately fail combination drug therapies. Insufficientdrug potency, non-compliance, restricted tissue penetration anddrug-specific limitations within certain cell types (e.g. mostnucleoside analogs cannot be phosphorylated in resting cells) mayaccount for the incomplete suppression of sensitive viruses.Furthermore, the high replication rate and rapid turnover of HIV-1combined with the frequent incorporation of mutations, leads to theappearance of drug-resistant variants and treatment failures whensub-optimal drug concentrations are present (Larder and Kemp; Gulick;Kuritzkes; Morris-Jones et al; Schinazi et al; Vaccaand Condra; Flexner;Berkhout and Ren et al; (Ref 6-14)). Therefore, novel anti-HIV agentsexhibiting distinct resistance patterns, and favorable pharmacokineticas well as safety profiles are needed to provide more treatment options.

Currently marketed HIV-1 drugs are dominated by either nucleosidereverse transcriptase inhibitors or peptidomimetic protease inhibitors.Non-nucleoside reverse transcriptase inhibitors (NNRTIs) have recentlygained an increasingly important role in the therapy of HIV infections(Pedersen & Pedersen, Ref. 15). At least 30 different classes of NNRTIhave been described in the literature (De Clercq, Ref. 16) and severalNNRTIs have been evaluated in clinical trials. Dipyridodiazepinone(nevirapine), benzoxazinone (efavirenz) and bis(heteroaryl) piperazinederivatives (delavirdine) have been approved for clinical use. However,the major drawback to the development and application of NNRTIs is thepropensity for rapid emergence of drug resistant strains, both in tissuecell culture and in treated individuals, particularly those subject tomonotherapy. As a consequence, there is considerable interest in theidentification of NNRTIs less prone to the development of resistance(Pedersen & Pedersen, Ref. 15).

Certain azaindole derivatives have demonstrated inhibitory activityagainst HIV. Such compounds, include the compound of formula 8:

which is disclosed in U.S. Pat. No. 6,476,034, herein incorporated byreference in its entirety.

In order to promote the development and production of effective newdrugs and treatments for HIV, such as the compounds of U.S. Pat. No.6,476,034, new methods of preparing these drugs which are more cost andtime efficient are required. The present invention seeks to provide suchmethods.

SUMMARY OF THE INVENTION

One aspect of the present invention provides a method of preparingcompounds of formula 25:

The method of preparing the compound of formula 25 includes the stepsof:

-   -   (a) converting a compound of formula 20:

to a compound of formula 22:

-   -   (b) converting the compound of formula 22 to a compound of        formula 23:    -   (c) coupling the compound of formula 23 with a compound of        formula 24:

Another aspect of the present invention provides a method of preparing acompound of formula 8:

Other aspects of the invention, including methods of preparing usefulintermediates, are also provided in each step below. The method ofpreparing the compound of formula 8 includes the steps of:

-   -   (a) converting a compound of formula 1:

to a compound of formula 2:

-   -   (b) converting said compound of formula 2 to a compound of        formula 3:    -   (c) converting said compound of formula 3 to a compound of        formula 4:    -   (d) converting said compound of formula 4 to a compound of        formula 5:    -   (e) cyclizing said compound of formula 5 to a compound of        formula 6:    -   (f) converting said compound of formula 6 to a compound of        formula 7:        ; and    -   (g) coupling said compound of formula 7 with a compound of        formula 9:

Another aspect of the present invention provides a method of isolatingand crystallizing the compound of formula 8 from the reaction mixturethat results from step (g). This method includes the introduction ofN-methylpyrrolidone (NMP) and water to the mixture including thecompound of formula 8. After the compound of formula 8 is isolated, itmay then be recrystallized using an isopropyl alcohol/waterrecrystallization solvent.

DETAILED DESCRIPTION OF THE INVENTION

The present invention relates to a method of preparing compounds offormula 25:

is selected from the group consisting of

R₁, R₂, R₃, R₄ are each independently selected from the group consistingof H, C₁-C₆ alkyl, C₃-C₆ cycloalkyl, C₂-C₆ alkenyl, C₄-C₆ cycloalkenyl,C₂-C₆ alkynyl, halogen, CN, phenyl, nitro, C(O)R₁₅, C(O)OR₁₆,C(O)NR₁₇R₁₈, OR₁₉, SR₂₀ and NR₂₁R₂₂;

R₁₅, is independently selected from the group consisting of H, C₁-C₆alkyl, C₃-C₆ cycloalkyl, C₂-C₆ alkenyl, and C₄-C₆ cycloalkenyl;

R₁₆, R₁₉, and R₂₀ are each independently selected from the groupconsisting of H, C₁-C₆ alkyl, C₃-C₆ cycloalkyl, C₂-C₆ alkenyl, C₄-C₆cycloalkenyl, C₃-C₆ alkynyl provided the carbons which comprise thecarbon-carbon triple bond of said C₃-C₆ alkynyl are not the point ofattachment to the oxygen or sulfur to which R₁₆, R₁₉, or R₂₀ isattached;

R₁₇ and R₁₈ are each independently selected from the group consisting ofH, C₁-C₆ alkyl, C₃-C₆ cycloalkyl, C₃-C₆ alkenyl, C₄-C₆ cycloalkenyl, andC₃-C₆ alkynyl provided the carbons which comprise the carbon-carbondouble bond of said C₃-C₆ alkenyl or the carbon-carbon triple bond ofsaid C₃-C₆ alkynyl are not the point of attachment to the nitrogen towhich R₁₇ and R₁₈ is attached;

R₂₁, and R₂₂ are each independently selected from the group consistingof H, C₁-C₆ alkyl, C₃-C₆ cycloalkyl, C₃-C₆ alkenyl, C₅-C₆ cycloalkenyl,C₃-C₆ alkynyl and C(O)R₂₃ provided the carbons which comprise thecarbon-carbon double bond of said C₃-C₆ alkenyl, C₄-C₆ cycloalkenyl, orthe carbon-carbon triple bond of said C₃-C₆ alkynyl are not the point ofattachment to the nitrogen to which R₂, and R₂₂ is attached;

R₂₃ is selected from the group consisting of H, C₁-C₆ alkyl, C₃-C₆cycloalkyl, C₂-C₆ alkenyl, C₄-C₆ cycloalkenyl, and C₂-C₆ alkynyl;

R₅ is (O)_(m), wherein m is 0 or 1;

n is 1 or 2;

R₆ is selected from the group consisting of H, C₁-C₆ alkyl, C₃-C₆cycloalkyl, C₄-C₆ cycloalkenyl, C(O)R₂₄, C(O)OR₂₅, C(O)NR₂₆R₂₇, C₃-C₆alkenyl and C₃-C₆ alkynyl, provided the carbons which comprise thecarbon-carbon double bond of said C₃-C₆ alkenyl or the carbon-carbontriple bond of said C₃-C₆ alkynyl are not the point of attachment to thenitrogen to which R6 is attached;

R₂₄ is selected from the group consisting of H, C₁-C₆ alkyl, C₃-C₆cycloalkyl, C₃-C₆ alkenyl, C₄-C₆ cycloalkenyl, and C₃-C₆ alkynyl;

R₂₅ is selected from the group consisting of C₁-C₆ alkyl, C₃-C₆cycloalkyl, C₂-C₆ alkenyl, C₄-C₆ cycloalkenyl, and C₃-C₆ alkynyl,provided the carbons which comprise the carbon-carbon triple bond ofsaid C₃-C₆alkynyl are not the point of attachment to the oxygen to whichR₂₅ is attached;

R₂₆ and R₂₇ are each independently selected from the group consisting ofH, C₁-C₆ alkyl, C₃-C₆ cycloalkyl, C₃-C₆ alkenyl, C₅-C₆ cycloalkenyl, andC₃-C₆ alkynyl provided the carbons which comprise the carbon-carbondouble bond of said C₃-C₆ alkenyl, C₅-C₆ cycloalkenyl, or thecarbon-carbon triple bond of said C₃-C₆ alkynyl are not the point ofattachment to the nitrogen to which R₂₆ and R₂₇ are attached;

R₇, R₈, R₉, R₁₀, R₁₁, R₁₂, R₁₃, and R₁₄ are each independently selectedfrom the group consisting of H, C₁-C₆ alkyl, C₃-C₆ cycloalkyl, C₂-C₆alkenyl, C₄-C₆ cycloalkenyl, C₂-C₆ alkynyl, CR₂₈R₂₉OR₃₀, C(O)R₃₁,CR₃₂(OR₃₃)OR₃₄, CR₃₅NR₃₆R₃₇, C(O)OR₃₈, C(O)NR₃₉R₄₀, CR₄₁R₄₂F₂ CR₄₃F₂ andCF₃;

R₂₈, R₂₉, R₃₀, R₃₁, R₃₂, R₃₅, R₄₁, R₄₂ and R₄₃ are each independentlyselected from the group consisting of H, C₁-C₆ alkyl, C₃-C₆ cycloalkyl,C₂-C₆ alkenyl, C₄-C₆ cycloalkenyl, C₂-C₆ alkynyl and C(O)R₄₄;

R₃₃, R₃₄ and R₃₈ are each independently selected from the groupconsisting of H, C₁-C₆ alkyl, C₃-C₆ cycloalkyl, C₃-C₆ alkenyl, C₄-C₆cycloalkenyl, and C₃-C₆ alkynyl, provided the carbons which comprise thecarbon-carbon triple bond of said C₃-C₆ alkynyl are not the point ofattachment to the oxygen to which R₃₄ and R₃₈ are attached;

R₃₆ and R₃₇ are each independently selected from the group consisting ofH, C₁-C₆ alkyl, C₃-C₆ cycloalkyl, C₃-C₆ alkenyl, C₄-C₆ cycloalkenyl, andC₃-C₆ alkynyl, provided the carbons which comprise the carbon-carbontriple bond of said C₃-C₆ alkynyl are not the point of attachment to thenitrogen to which R₃₆ and R₃₇ are attached;

R₃₉ and R₄₀ are each independently selected from the group consisting ofH, C₁-C₆ alkyl, C₃-C₆ cycloalkyl, C₂-C₆ alkenyl, C₄-C₆ cycloalkenyl, andC₃-C₆ alkynyl, provided the carbons which comprise the carbon-carbontriple bond of said C₃-C₆ alkynyl are not the point of attachment to thenitrogen to which R₃₉ and R₄₀ are attached;

R₄₄ is selected from the group consisting of H, C₁-C₆ alkyl, C₃-C₆cycloalkyl, C₂-C₆ alkenyl, C₄-C₆ cycloalkenyl, and C₂-C₆ alkynyl;

Ar is selected from the group consisting of

A₁, A₂, A₃, A₄, A₅, B₁, B₂, B₃, B₄, C₁, C₂, C₃, D₁, D₂, and D₃ are eachindependently selected from the group consisting of H, CN, halogen, NO₂,C₁-C₆ alkyl, C₃-C₆ cycloalkyl, C₂-C₆ alkenyl, C₄-C₆ cycloalkenyl, C₂-C₆alkynyl, OR₄₅, NR₄₆R₄₇, S₄₈, N₃ and CH(—N═N—)—CF₃;

R₄₅ is selected from the group consisting of H, C₁-C₆ alkyl, C₃-C₆cycloalkyl, C₂-C₆ alkenyl, C₄-C₆ cycloalkenyl and C₃-C₆ alkynyl,provided the carbons which comprise the carbon-carbon triple bond ofsaid C₃-C₆ alkynyl are not the point of attachment to the oxygen towhich R₄₅ is attached;

R₄₆ and R₄₇ are each independently selected from the group consisting ofH, C₁-C₆ alkyl, C₃-C₆ cycloalcyl, C₃-C₆ alkenyl, C₅-C₆ cycloalkenyl,C₃-C₆ alkynyl and C(O)R₅₀, provided the carbons which comprise thecarbon-carbon double bond of said C₅-C₆ alkenyl, C₄-C₆ cycloalkenyl, orthe carbon-carbon triple bond of said C₃-C₆ alkynyl are not the point ofattachment to the nitrogen to which R₄₆ and R₄₇ are attached;

R₄₈ is selected from the group consisting of H, C₁-C₆ alkyl, C₃-C₆cycloalkyl, C₂-C₆ alkenyl, C₄-C₆ cycloalkenyl, C₃-C₆ alkynyl andC(O)R₄₉, provided the carbons which comprise the carbon-carbon triplebond of said C₃-C₆ alkynyl are not the point of attachment to the sulfurto which R₄₈ is attached;

R₄₉ is C₁-C₆ alkyl or C₃-C₆ cycloalkyl;

R₅₀ is selected from the group consisting of H, C₁-C₆ alkyl, and C₃-C₆cycloalkyl.

R₇₅ is selected from the group consisting of H and CH₃; and

R₇₆ is selected from the group consisting of C₁-C₃ alkoxy and halogen.

Examples of similar compounds are set forth in commonly assigned PatentApplication No. WO 01/62255 and U.S. Pat. No. 6,476,034, the disclosureof each being incorporated herein in its entirety.

One aspect of the present invention is shown below in Scheme 1.

The sequence of reactions in Scheme 1 shows a general approach to thesynthesis of compounds of formula 25. In step 1, compound 20 isconverted to bicyclic compound 22 through one two pathways, a or b. Instep 2, a mono- or di-carbonyl moiety is added, forming compound 23.Compound 23 is then coupled with compound 24.

As shown, compound 22 may be obtained from compound 20 via two pathways.Thus, step 1 of Scheme 1 may proceed through the pathway of step 1(a) orstep 1 (b). Depicted below in Sheme 1(a) is step 1(a).

As can be seen, compound 20(a), in which substituent R₇₅ is methyl, isreacted under basic conditions with an acetal to form intermediate 21.Enamine 21 is then cyclized to compound 22 via catalytic hydrogenation.

Alternatively, compound 22 may be obtained via the pathway depicted inScheme 1(b).

Scheme 1(b) shows the second pathway along which compound 22 may beobtained from compound 20. Particularly, when substituent R₇₅ ishydrogen, shown here as compound 20(b), compound 22 may be obtained viareaction with a vinyl magnesium halide.

Scheme 2 depicts addition of a carbonyl group to compound 22, resultingin compound 23(a).

Alternatively, a di-carbonyl group may be used, as shown at the bottomof Scheme 2, resulting in di-carbonyl compound 23(b).

Scheme 3 below depicts coupling of compounds 23 and 24.

Accordingly, one aspect of the present invention relates to a method forpreparing compounds of formula 25 through the steps of:

-   (a)(1) converting a compound of formula 20(a):

to a compound of formula 21:

-   (a)(2) converting the compound of formula 21 to a compound of    formula 22:    -   (b) converting the compound of formula 22 to a compound of        formula 23:    -   (c) coupling the compound of formula 23 with a compound of        formula 24:

More particularly, such a conversion is accomplished through the stepsof:

-   (a) reacting a compound of formula 20(a):

in the presence of a base, with

to form a compound of formula 21:

catalytically hydrogenating the compound of formula 21 to form acompound of formula 22:

-   -   (b) reacting the compound of formula 22, in the presence of a        Lewis acid—, with

to form a compound of formula 23:

-   -   (c) reacting the compound of formula 23, in the presence of a        base, with a compound of formula 24:

Alternatively, compounds of formula 25 may be prepared via the steps of:

-   a) converting a compound of formula 20(b):

to a compound of formula 22:

-   -   (b) converting the compound of formula 22 to a compound of        formula 23:    -   (c) coupling the compound of formula 23 with a compound of        formula 24:

More particularly, the conversion via these steps is accomplishedthrough:

-   (a) reacting a compound of formula 20(b):

to give a compound of formula 22:

-   -   (b) reacting the compound of formula 22, in the presence of a        Lewis acid, with

to form a compound of formula 23:

-   -   (c) reacting the compound of formula 23, in the presence of a        base, with a compound of formula 24:

Another aspect of the present invention is shown in detail below inScheme 2, and in the detailed steps 1-7, which follow.

The sequence of reactions in Scheme 4 shows a general organization ofthe steps from the starting material of compound 1 to the final stepresulting in the compound of formula 8. As is shown below, each of thesteps may include different reaction conditions to achieve the desiredproduct. This is further shown in the examples, below. Each of the stepsare described by corresponding numbers as shown in Scheme 4. Each of theconsecutive steps below uses the end product of the previous reaction asthe starting material of the next step.

Step 1, the conversion of the compound of formula 1 to the compound offormula 2 is achieved through the introduction of bromine (Br₂) inacetic acid (AcOH). The amount of bromine is in the range of about 0.5to about 2 equivalents (eq.).

Step 2 is conducted with the addition of tert-butyl nitrite(t-Bu-Nitrite) in the presence of an acid. The acid may be generated insitu using acetyl chloride and alcohol. The reaction is exothermic andtherefore cooling may be added as necessary. Also, to neutralize acid atthe end of the reaction sodium bicarbonate solution may be added.

Step 3 includes the use of N,N-dimethyl formamide-dimethyl acetal inaddition to dimethyl formamide (DMF) as a solvent and lithium methoxide(LiOMe) in methanol (MeOH). The reaction is endothermic. Therefore, heatmay be added as necessary.

Step 4 is also a slightly exothermic reaction. Copper iodide (Cul) isadded in a range of 0.05 to 0.8 eq., desirably from 0.2 to about 0.3 eq.This is followed by the addition of methyl propionate (EtCOOMe) (fromabout 5 to about 20 eq.), tetrahydrofuran (THF) (from about 5 to about20 eq.), and sodium methoxide (NaOMe) (from about 5 to about 25 eq.).The reaction mixture is heated to reflux temperature (65° C. to about75° C.) until the reaction is complete.

Step 5 is the cyclization of the compound of formula 5 to the compoundof formula 6 by reduction reaction. A variety of catalysts are usefulfor this including palladium over carbon (Pd/C), Pd—C transferhydrogenation conditions, and precious metal catalysts such as Pt/Cavailable as Escat 261 or Escat 160 from Englehard (reductions can alsobe done using other metals such as Zn, Fe, etc. as well as with sodiumdithionate). The reaction is conducted in the presence of ethyl acetate(EtOAc) under hydrogen (H₂) pressure in a range from about 10 PSI toabout 50 PSI.

Step 6, which represents conversion of the compound of formula 6 to thecompound of formula 7, is also includes slightly exothermic reactionswhich may be controlled by the addition rate. Specifically, afteraluminum chloride and the compound of formula 6 is added to a reactorincluding dichloromethane (CH₂Cl₂) in portions, nitromethane (CH₃NO₂) isthen added followed by methyl chlorooxacetate (ClCOCOOMe) in a rangefrom about 1.0 eq. to about 5.0 eq. The exothermic reaction iscontrolled by the addition rate of chlorooxacetate. This step mayoptionally be followed by quenching with a suitable reagent. It has beenobserved that favorable results were obtained using a preferredembodiment of the process in which first water, and then ammoniumacetate are added to quench the reaction mixture.

In Step 7, the compound of formula 7 is coupled with the compound offormula 9 to provide the compound of formula 8. This reaction may, incertain embodiments, be conducted in the presence of sodiumtert-butoxide (NaOtBu) in tetrahydrofuran, whereupon improvedsignificantly improved yields, up to about 90% by weight based on totalweight of the reaction mixture, may be obtained. HCl may be added afterthe coupling reaction to neutralize the pH.

The product of step 7, i.e., the compound of formula 8 is then isolatedand recrystallized using N-methylpyrrolidone and water. This removesmany impurities. A second recrystallization may then be performed toreduce the amount of NMP and achieve a control over the particle size inthe final product. This may be performed with a recrystallizationsolvent including isopropyl alcohol (EPA) and water.

The features and advantages of the present invention are more fullyshown by the following examples which are provided for purposes ofillustration, and are not to be construed as limiting the invention inany way.

EXAMPLES Example 1 Step 1

A reaction vessel was purged with inert gas. All steps were performedunder inert gas protection.

The vessel was then charged with 7.50 L of acetic acid at 20-25° C.Next, 1.00 kg of the compound of formula 1 was added to the vessel. Ayellow suspension was formed. This was followed by the addition of 1.07kg of sodium acetate. A very thick, yellow suspension was formed and thereaction was noted to be slightly exothermic. The temperature was raisedto about 27° C.

The mixture was then cooled to about 15-20° C. and a sample was takenfor high pressure liquid chromatography (HPLC) monitoring.

A solution of 1.15 kg of bromine (1.1 eq.) and 2.5 L of acetic acid wasprepared. A 10/11 portion of the solution, i.e., 1.0 eq. at 15-20° C.was added to the vessel over about 10-15 minutes. the addition wasslightly exothermic and some cooling was necessary (T_(max)=20° C.).HPLC was used to monitor the reactions progress immediately after theaddition and then at 60 min. Less than 10% of the starting material wasobserved. Then the remainder of the solution was added and the reactionmixture stirred until completion, approximately 30-60 additionalminutes.

After the reaction was complete 10.0 L of ice water was added, droppingthe temperature to 10° C. and forming a suspension. The suspension wasstirred for another 30-60 minutes and the product was filtered, thenwashed three times with 2.50 L each time of ice water. The product wasdried in at a maximum temperature of 40° C. until reaching constantweight. The yield was 1.45 kg (96.00%) yellow crystals.

Analytical data: m.p. 132° C. IR (KBr, cm⁻¹): 1633, 1581, 1538, 1512,1458, 1377, 1344, 1321, 1244, 869, 779. ¹H-NMR (CDCl₃) (δ, ppm): 2.55(s, 3H), 5.85 (bs, 2H), 8.25 (s, 1H): ¹³C-NMR (CDCl₃) (δ, ppm): 20.81,112.14, 144.49, 151.91, 153.78 (2C); MS ; (M+1): 232; ElementalAnalysis: calcd for C₆H₆BrN₃O₂: C 31.05, H 2.60, N 18.11, Br 34.43;found: C 30.95, H 2.42, N 17.45, Br 34.80.

Example 2 Step 2

This reaction was conducted under inert gas protection.

The reaction vessel was first charged with 2000 ml methanol and cooledto about 0° C. with slight agitation. Then 9.1 kg acetyl chloride wasadded. The exothermic reaction was then cooled and agitated for 10minutes.

The next addition was 100 g 2-amino-5-bromo-3-nitro-4-picoline (thecompound of formula 2 at 0° C. Then 236.5 g of t-butyl nitrite was addedat a rate such that the temperature did not exceed 5° C. The slightevolution of nitrogen gas was noted. After the completion of thereaction, cooling was removed and the reaction mixture within the vesselwas allowed to warm to 25° C. in about 30 minutes.

The mixture was agitated at 25° C. for about 3-4 hours. After 4-5 hoursa clear solution was obtained. Reaction completeness was monitored byHPLC after about 4 hours. The reaction was complete after about 5 hours.

The reaction mixture was concentrated in vacuo to about 1000 mL. Then500 ml of water was added and the product precipitated. Then 250 mlsaturated sodium bicarbonate solution was added with good agitation toneutralize the HCl and dissolve the hydroxy impurity. The mixture wasagitated at 20-25° C. for about 15 minutes and then the precipitate wascollected and washed with 1000 ml of water. The product was then driedat 40° C. in vacuo. Yield was 75.0 g.

Analytical data: m.p. 132° C. IR (KBr, cm⁻¹): 1633, 1581, 1538, 1512,1458, 1377, 1344, 1321, 1244, 869, 779. ¹H-NMR (DMSO-d6) (δ, ppm): 2.31(s, 3H), 3.96 (s, 3H), 8.55 (s, 1H): ¹³C-NMR (DMSO-d6) (δ, ppm): 17.49,54.91, 99.41, 114.39, 141.02, 149.23, 153.46; HRMS calcd for C₇H₇BrN₂O₃245.96401 found (M+1): 246.97184; Elemental Analysis: calcd forC₇H₇BrN₂O₃: C 34.03, H 2.85, N 11.34; found: C 33.81, H 2.91, N 11.24.

Example 3 Step 3

The reaction vessel was purged with inert gas and all steps wereperformed under inter gas protection.

The vessel was charged with 100 g of the compound of formula 3. Then 800mL of dimethyl formamide (DMF) was added followed by 39.5 mL of 1.0 Msolution of LiOMe in MeOH (32.25 g, 0.0395 mmol). The reaction washeated to 80° C.

The next addition to the vessel was 430.17 mL N,N-dimethylformamide-dimethyl acetal (3.23 mmol, 8 eq.) over 10 minutes. Anendothermic reaction was noted. The reaction was heated to 95° C. andcompleted in about 8-10 hours as confirmed by HPLC. After the reactionwas complete, it was cooled to room temperature. 1200 mL water wasadded, while maintaining the temperature of the reaction mixture aboveabout 40° C.

A red solid precipitated which was filtered and then washed with two 300mL portions of water. The product was dried to obtain the compound offormula 4. Karl Fischer (KF) titration revealed the water content to beabout 0.08-0.11%.

Analytical data: m.p. 132° C. IR (KBr, cm⁻¹): 1629, 1582, 1487, 1407,1309, 1081. ¹H-NMR (CDCl₃) (δ, ppm): 2.92 (s, 6H), 3.94 (s, 3H), 4.92(d,1H), 7.0 (d, 1H), 8.15 (s, 1H): ¹³C-NMR (CDCl₃) (δ, ppm): 54.79,87.94,112.08, 140.15, 147.59, 148.57, 155.03; MS calcd for C₁₀H₁₂BrN₃O₃ 301.01found (M+1): 302.0.

Example 4 Step 4

The reaction vessel was purged with inert gas and then charged with 250g (0.827) of the compound of formula 4, then 31.52 g CuI (0.165 mol, 0.2eq.), 875 mL methyl propionate (about 9.102 mol, 11 eq.), 875 mLtetrahydroflran (about 10.787 mol, 13 eq.), and 2838 mL NaOMe (25% inMeOH)(12.412 mol, 15 eq.). Exothermic reaction was noted, 21° C. toabout 27° C. The reaction was heated to reflux temperature (about 69-71°C.) until the reaction was complete (about 20 hours).

The reaction mixture was cooled to around 5° C. Then the vessel wascharged with 4960 mL of 3.7 M NH₄Cl (aq.)(about 3.5-3.9M). Exothermicreaction was noted (about 26° C. to about 29° C.) and pH changed fromabout 13.0-13.5 to about 9.2-9.7.

The reaction mixture was filtered to collect the precipitate. Theproduct was then washed until the washings were free of halide (AgNO₃test negative). The product was then dried under vacuum oven at 50° C.until KF<0.1% obtaining 165.3 g of the compound of formula 5.

Analytical data: m.p. 167-168 ° C. IR (KBr, cm⁻¹): 1629, 1582, 1487,1408, 1309, 1081. ¹H-NMR (DMSO-d6) (δ, ppm): 2.87 (s, 6H), 3.82 (s, 3H),3.89 (s, 3H), 4.51 (d, 1.2 Hz, 1H), 7.74 (s, 1H), 7.83 (d, 1.5 Hz, 1H).¹³C-NMR (DMSO-d₆) (δ, ppm): 53.6, 56.8, 82.2, 128.6, 130.2, 131.2,146.6, 148.9, 150.3. HR-MS: calcd for C₁₁H₁₆N₃O₄ (M+H⁺): 254.1141;found: 254.1138. Elemental Analysis: calcd for C₁₁H₁₅N₃O₄: C 52.16, H5.97, N 16.59; found: C 51.91, H 5.73, N 16.43.

Example 5 Step 5

The compound of formula 5 (15 g) was charged into a 1 L glass buchiihydrogenation reactor followed by 1.5 g of Escat-261 (1% Pt/C, ˜59%wet), 300 mL of ethyl acetate, and the reactor was purged three timeswith nitrogen (25 PSI each). The first purge was without stirring,followed by second and third with 100-200 rpm stirring. Then the reactorwas purged three times, while stirring with hydrogen gas and the reactorwas pressurized at 25 PSI with hydrogen at 25° C. internal temperature.

The reaction RPM was set to 800 and the hydrogen uptake was followed.The reaction was stopped with the hydrogen uptake stabilized. An aliquotwas diluted at 100× and tested by HPLC to test completion as well asproduct to impurity ratio.

The catalyst was filtered off and the filtrate washed with 10 mL ethylacetate. Then to the filtrate was added 150 mL of deionized water (DIwater) and stirred for 20 minutes. Then 7.11 mL of acetic acid was addedand stirred for 30 minutes. The mixture was allowed to separate and theslightly pinkish aqueous layer was removed. Two more additions of 150 mLof DI water were introduced to the organic layer and stirred for 30minutes followed by separating and removing the aqueous layer.

The last two removed aqueous layers were combined and stirred with 50 mLethyl acetate for 20 minutes. The organic layer was removed and combinedwith the original organic layer. The total organic layer was transferredto a 1 L 3-necked flask with mechanical stirrer. 16 mL isopropanol (EPA)was added followed by 7.7 mL of TMSCl added dropwise at room temperatureover a ten minute period. The resulting slurry was stirred for one hourat room temperature then filtered and the filtrate washed with two 20 mLportions of ethyl acetate. The cake was dried at 40° C. in a vacuum ovenfor 15 hours. The yield was white solid 11.09 g.

Analytical data: m.p. 294.81° C. IR (KBr, cm⁻¹): 1629, 1582, 1487, 1408,1309, 1081. ¹H-NMR (DMSO-d₆) (δ, ppm): 3.90 (s, 3H), 4.20 (s, 3H), 6.58(bs, 1H), 7.12 (s, 1H), 7.74 (bs, 1H). ¹³C-NMR (DMSO-d₆) (δ, ppm):56.41, 58.06, 100.83, 107.13, 107.17, 119.84, 128.61, 132.20, 145.61,145.75. MS: calcd for C₉H₁₀N₂O₂: 178.07; found: 179 (M+1).

Example 6 Step 6

The reaction was conducted under nitrogen blanket. A reactor was chargedwith 27.7 g AlCl₃ (4.4 eq.) followed by 180 mL dichloromethane withargon protection. The reaction mixture was cooled to about −20° C. withagitation. Then the compound of formula 6 (HCl-salt) (10.00 g) was addedin portions, rinsed with 20 mL dichloromethane and stirred for 15minutes. A slight exothermic reaction was noted and the temperaturerange was controlled in a range from about −15° C. to about −20° C.

The next addition was 34.0 mL nitromethane, added dropwise, then rinsedwith 10 mL dichloromethane, while maintaining the temperature from about−15° C. to about 20° C. controlled by the addition rate. The mixture wasagitated for 5 minutes.

Fifteen (15.0) mL of methyl chlorooxoacetate was then added at a ratesuch that the temperature did not exceed −15° C. and rinsed with 10 mLdichloromethane. After the addition, the mixture was agitated at −20°for 30 minutes and a sample was taken for HPLC.

A solution was prepared including 50 g ammonium acetate in 200 mL waterand 50 mL of dichloromethane. The solution was cooled to about 0 toabout −5° C. The solution was then combined with the reaction mixturekeeping the temperature below about 15° C.

The reactor was rinsed with a mixture of 20 mL CH₂Cl₂ and 20 mL water.The product is in the lower organic phase. The upper aqueous phase wasextracted with 50 mL dichloromethane and the organic phases werecombined. The organic phase was then treated with vacuum to speed thedistillation off of the dichloromethane, reducing the volume to about80-100 mL. Under the continuous vacuum, 240 mL of isopropyl alcohol wasadded, then distilled to a final volume of 8 mL/g. After thedistillation, the reaction mixture is brought to about 50° C.

A separate (second) reactor was charged with 30 mL isopropanol andcooled to 0° C. Then, 3 mL acetyl chloride was added and agitated for 30minutes. An exotherm of 10-12° C. was observed.

To the solution in the first reactor, 10 mL of the solution in thesecond reactor was added dropwise over 5 minutes to inducecrystallization. The mixture was held at 50° C. for 20 minutes, then theremaining solution from the second reactor was added.

Following the reaction, the mixture was cooled to room temperature andagitated for one hour. Then the mixture was cooled to 0-5° C. andagitated for about one hour. The precipitate was collected and washedwith 70 mL IPA. The compound was dried until the loss on drying (LOD)was less than about 0.3%. The yield was about 75-80%.

Analytical data: mp 147.4-149.6° C. (dec); ¹H NMR: (DMSO-d6, ppm) δ13.26 (br s, 1H), 9.07-9.50 (br, 1H), 8.28 (d, J=3.3 Hz, 1H), 7.45 (s,1H), 4.02 (s, 3H), 3.84 (s, 3H), 3.83 (s, 3H); ¹³C NMR: (DMSO-d6, ppm) δ181.50, 164.87, 146.35, 145.72, 137.55, 123.85, 121.91, 115.68, 113.91,56.94, 55.42, 52.56; Elemental analysis: Calc: C 47.93, H 4.36, N 9.32,Cl 11.79. Found: C 47.66, H 4.58, N 9.20, Cl 11.66.

Example 7 Step 7 Including Isolation and Recrystallization

Into a 300 mL mini-reactor was charged 12.0 g of the compound of formula7 and 9.95 g of the compound of formula 9, followed by 137 mL of THF.The mixture was stirred to give a slurry, then cooled to −5 to 5° C.with stirring. Then 59.1 mL 30 wt % NaOtBu was added to the slurrykeeping the temperature below 10° C.

HPLC was monitored for completion of the reaction which was complete inabout 2.5 hours. The reaction mixture was then transferred by vacuum to72 mL water in a 500 mL mini reactor. The mixture was stirred for 30minutes to hydrolyze the residual starting material.

Then 72 mL of IN HCl was added over 2 minutes (pH 9.23). The HCl wasadded in 1 mL portions to pH 6.75 (a total of 86 mL 1N HCl). The mixturewas biphasic solution before and after neutralization.

130 mL of THF was evaporated and solids started to precipitate; temp ofpot 68° C., vapor 64° C., jacket set at 80° C.). NMP (72 mL) was thenadded. The solids did not all dissolve but darker colored material onthe walls of the reactor dissolved (presumably impurities). Theevaporation was continued until 192 mL of distillate had been collectedand distillation was much slower; calculated volume of distillateexpected 207 mL. Final temperatures were: jacket 105° C., pot 89° C.,vapor 79° C.

The mixture was cooled to room temp over one hour and stirred at roomtemperature for 18 hours. Then the mixture was cooled to 0-5° C. overone hour and stirred at 0° C. for two hours. The product was collectedand rinsed with 4×24 water and then dried.

Analytical data: mp 243-245° C.; ¹H NMR: (DMSO-d6, ppm) δ12.98 (s, 1H),8.14 (d, J=2.5 Hz, 1H), 7.47 (bs, 6H), 3.99 (s, 3H), 3.84 (s, 3H), 3.64(bs, 4H), 3.38 (bs, 4H); ¹³C NMR: (DMSO-d6, ppm) δ 186.32, 170.01,167.26, 146.96, 146.54, 137.29, 136.26, 130.38, 129.13, 127.74, 123.05,122.90, 120.12, 115.21, 57.66, 53.63, 45.89, 41.27; Elemental analysis:Calc: C 62.55, H 5.24, N 13.26. Found: C 62.28, H 5.14, N 13.17.

Example 8 Isolation and Recrystallization of Formula 8

Balanced Side Reaction

The pH was adjusted with 6N HCl to achieve a pH of about 6.5.

Then the reaction mixture was heated from 6.6° C. to 61.5° C. over 70minutes to begin the distillation. The level in the reactor wasmaintained by charging NMP. The distillation temperature reached amaximum at the end of the distillation at 89.8° C. The batch was thenassayed by GC to find 1.85% THF, 1.42% t-BuOH and 31.55% NMP by volume.

Water was then charged which was pre heated to 70.1° C., thentransferred to the reaction mixture over 18 min. The batch temperaturewas maintained at 77° C. through the transfer. The batch was then heldfor 37 minutes at 74.6° C. to 77° C. Cooling was initiated slowly,bringing the slurry from 74.6° C. to 10.0° C. over 3 hours and 9minutes. It was then held for 62 minutes from 6.3° C. to 10.0° C. Afiltered sample showed the mother liquor to have 5.23 mg/ml of formula 8and 3.88 mg/ml of formula 9.

Isolation:

The product was isolated on centrifuge. The composite KF of the wet cakewas 4.97%.

Drying:

The cake was dried in the tray dryer. Heat and vacuum were appliedaveraging 35.6° C. and 22.8 mmHg, respectively. After 12 hours, productwas dry and had representative moisture contents ranging from 1.74% to2.15% KF.

Recrystallization:

In a reactor 18.56 kg of the compound of formula 8 was charged, followedby 280.4 kg EPA/water recrystallization solvent, charged over 23minutes. The reactor was heated from 28.8° C. to 78.8° C. over 2 hours28 minutes and stirred in the 78.8 to 80.2° C. temperature range for 21minutes. An additional 23.7 kg recrystallization solvent rinse wascharged, and the mixture held for 5 hours 11 minutes between 78.8 and81.4° C. The seed slurry was prepared by charging 0.191 kg of thecompound of formula 8 to a carboy, followed by 1.5 kg Isopropanol.Reactor was heated to 60° C., and the batch transferred over 30 minutesthrough polish filter F57 into Reactor. The batch temperature was 67.9°C. after the transfer. The batch was cooled from 68.2° C. to 42.3° C.over 62 minutes. The slurry of seeds was added over 2 minutes and thebatch cooled to 20° C. over 36 minutes. The batch was held for 15 hours45 minutes at ambient temperature.

Isolation/Drying:

The 363 L slurry was filtered over 13 minutes using Robatel 540 mmcentrifuge C-9 with a loading speed of 900 rpm and a deliquoring speedof 900 rpm using a 5-10 μm polypropylene bag. The material was washedwith 27.5 kg IPA and deliquored for 1 hour 36 minutes. The cakethickness in C9 was 6.2 cm for the 16.2 kg of wet cake isolated. TheLOD's of the wet cake at top, middle and bottom were 3.79, 3.71 and5.10% respectively.

Drying:

The cake was dried in the 316SS tray dryer D6 with 16.20 kg over 4trays. Heat and vacuum were applied averaging 45° C. and 21 mmHg,respectively. After 19 hours, the 15.37 kg of product was dry-havingrepresentative LODs ranging from 0.47% to 0.60%.

Delumping/Blending:

15.22 kg dry compound of formula 8 was milled at approximately 200 rpmusing M1(Quadro Comil fitted with round-end impeller) with screen size0.055″ over 45 minutes. The material was then blended in a 30-galcontainer for 35 minutes in GR-8 at 50 rpm to give 15.10 kg output ofdelumped and blended product.

The azaindole compounds prepared according to this invention havedemonstrated utility as antiviral agents that inhibit the HIV virus,alone, or in combination with other pharmaceutical agents and/orexcipients. Azaindole oxoacetic piperazine amides, and their usefulnessas HIV inhibitors, have been disclosed in two series of patentapplications. The first series discloses azaindole derivatives whichhave promising potential as antiviral agents, Wang, Tao et al., U.S.Pat. No. 6,476,034 and PCT Application WO 0162255 A1, filed Jan. 19,2001, published Aug. 30, 2001. The second series, Wang, Tao, et al.discloses HIV Antiviral Activity of Substituted AzaindoleoxoaceticPiperazine Derivatives in U.S. patent application Ser. No. 10/214,982filed Aug. 7, 2002, which is a continuation-in-part application of U.S.Ser. No. 10/038,306 filed Jan. 2, 2002 (corresponding to PCT Appl.(PCT/US02/00455), WO 02/062423 A1, filed Jan. 2, 2002, published Aug.15, 2002. The subject matter of all the abovementioned applications isincorporated by reference herein.

While there have been described what are presently believed to be thepreferred embodiments of the invention, those skilled in the art willrealize that changes and modifications may be made thereto withoutdeparting from the spirit of the invention, and it is intended toinclude all such changes and modifications as fall within the true scopeof the invention.

1. A method of preparing a compound of formula 8:

comprising the steps of: (a) converting a compound of formula 1:

to a compound of formula 2:

(b) converting said compound of formula 2 to a compound of formula 3:

(c) converting said compound of formula 3 to a compound of formula 4:

(d) converting said compound of formula 4 to a compound of formula 5:

(e) cyclizing said compound of formula 5 to a compound of formula 6:

(f) converting said compound of formula 6 to a compound of formula 7:

; and (g) coupling said compound of formula 7 with a compound of formula9:


2. The method of claim 1, wherein said converting said compound offormula 1 to said compound of formula 2 is conducted with the additionof bromine and acetic acid.
 3. The method of claim 1, wherein saidconverting said compound of formula 2 to said compound of formula 3 isconducted with tert-butyl nitrite in the presence of acid.
 4. The methodof claim 1, wherein said converting said compound of formula 3 to saidcompound of formula 4 is conducted with N,N-dimethyl formamide-dimethylacetal in the presence of lithium methoxide in methanol and dimethylformamide.
 5. The method of claim 1, wherein said converting saidcompound of formula 4 to said compound of formula 5 is conducted in thepresence of copper iodide, methyl propionate, tetrahydrofaran, andsodium methoxide.
 6. The method of claim 1, wherein said cyclizing saidcompound of formula 5 to said compound of formula 6 is conducted with aprecious metal catalyst in the presence of ethyl acteate or Pd/C orcatalytic transfer hydrogenation or reduction with sodium dithonate. 7.The method of claim 6, wherein said precious metal catalyst comprisesPt/C.
 8. The method of claim 1, wherein said converting said compound offormula 6 to said compound of formula 7 is conducted with aluminumchloride followed by the addition of chloromethane, nitromethane, andchlorooxoacetate.
 9. The method of claim 1, wherein following step (f),the reaction is quenched with water, and then with ammonium acetate. 10.The method of claim 1, wherein said coupling the compound of formula 7with the compound of formula 9 is conducted in the presence of sodiumtert-butoxide and tetrahydrofuran.
 11. A method of preparing a compoundof formula 8:

comprising the step of coupling a compound of formula 7:

with a compound of formula 9:


12. The method of claim 11, wherein the yield of the compound of formula8 is up to about 90% weight, based on total weight of the reactionmixture.
 13. The method of claim 11, wherein said compound of formula 7is prepared by the steps of. (a) cyclizing a compound of formula 5:

to a compound of formula 6:

(b) converting said compound of formula 6 to said compound of formula 7.14. The method of claim 13, wherein said compound of formula 5 isprepared by the step of converting a compound of formula 4:

to said compound of formula
 5. 15. The method of claim 14, wherein saidcompound of formula 3 is prepared by the step of converting a compoundof formula 2:

to said compound of formula
 3. 16. A method of preparing a compound offormula 5:

comprising the step of converting a compound of formula 4:

to said compound of formula
 5. 17. The method of claim 14, wherein saidcompound of formula 4 is provided by: (a) converting a compound offormula 2:

to a compound of formula 3:

(b) converting said compound of formula 3 to said compound of formula 4.18. A method of preparing a compound of formula 2:

comprising the step of converting a compound of formula 1:

to said compound of formula
 2. 19. A method of isolating the compound offormula 8 as prepared in claim 1 comprising the steps of: (a) distillinga product of step (g) in a reactor while charging withN-methylpyrrolidone to maintain volume; (b) charging said reactor withwater; and (c) isolating said product on centrifuge.
 20. The method ofclaim 19 further comprising the step of recrystallizing said productwith a mixture comprising isopropyl alcohol and water.
 21. A method ofpreparing the compound of formula 25:

comprising the steps of: (a) converting a compound of formula 20:

to a compound of formula 22:

(b) converting said compound of formula 22 to a compound of formula 23:

(c) coupling said compound of formula 23 with a compound of formula 24:

wherein, in each instance,

is selected from the group consisting of

R₁, R₂, R₃, R₄ are each independently selected from the group consistingof H, C₁-C₆ alkyl, C₃-C₆ cycloalkyl, C₂-C₆ alkenyl, C₄-C₆ cycloalkenyl,C₂-C₆ alkynyl, halogen, CN, phenyl, nitro, C(O)R₁₅, C(O)OR₁₆,C(O)NR₁₇R₁₈, OR₁₉, SR₂₀ and NR₂₁R₂₂; R₁₅, is independently selected fromthe group consisting of H, C₁-C₆ alkyl, C₃-C₆ cycloalkyl, C₂-C₆ alkenyl,and C₄-C₆ cycloalkenyl; R₁₆, R₁₉, and R₂₀ are each independentlyselected from the group consisting of H, C₁-C₆ alkyl, C₃-C₆ cycloalkyl,C₂-C₆ alkenyl, C₄-C₆ cycloalkenyl, C₃-C₆ alkynyl provided the carbonswhich comprise the carbon-carbon triple bond of said C₃-C₆ alkynyl arenot the point of attachment to the oxygen or sulfur to which R₁₆, R₁₉,or R₂₀ is attached; R₁₇ and R₁₈ are each independently selected from thegroup consisting of H, C₁-C₆ alkyl, C₃-C₆ cycloalkyl, C₃-C₆ alkenyl,C₄-C₆ cycloalkenyl, and C₃-C₆ alkynyl provided the carbons whichcomprise the carbon-carbon double bond of said C₃-C₆ alkenyl or thecarbon-carbon triple bond of said C₃-C₆ alkynyl are not the point ofattachment to the nitrogen to which R₁₇ and R₁₈ is attached; R₂₁ and R₂₂are each independently selected from the group consisting of H, C₁-C₆alkyl, C₃-C₆ cycloalkyl, C₃-C₆ alkenyl, C₅-C₆ cycloalkenyl, C₃-C₆alkynyl and C(O)R₂₃ provided the carbons which comprise thecarbon-carbon double bond of said C₃-C₆ alkenyl, C₄-C₆ cycloalkenyl, orthe carbon-carbon triple bond of said C₃-C₆ alkynyl are not the point ofattachment to the nitrogen to which R₂, and R₂₂ is attached; R₂₃ isselected from the group consisting of H, C₁-C₆ alkyl, C₃-C₆ cycloalkyl,C₂-C₆ alkenyl, C₄-C₆ cycloalkenyl, and C₂-C₆ alkynyl; R₅ is (O)_(m),wherein m is 0 or 1; n is 1 or 2; R₆ is selected from the groupconsisting of H, C₁-C₆ alkyl, C₃-C₆ cycloalkyl, C₄-C₆ cycloalkenyl,C(O)R₂₄, C(O)OR₂₅, C(O)NR₂₆R₂₇, C₃-C₆ alkenyl and C₃-C₆ alkynyl,provided the carbons which comprise the carbon-carbon double bond ofsaid C₃-C₆ alkenyl or the carbon-carbon triple bond of said C₃-C₆alkynyl are not the point of attachment to the nitrogen to which R₆ isattached; R₂₄ is selected from the group consisting of H, C₁-C₆ alkyl,C₃-C₆ cycloalkyl, C₃-C₆ alkenyl, C₄-C₆ cycloalkenyl, and C₃-C₆ alkynyl;R₂₅ is selected from the group consisting of C₁-C₆ alkyl, C₃-C₆cycloalkyl, C₂-C₆ alkenyl, C₄-C₆ cycloalkenyl, and C₃-C₆ alkynyl,provided the carbons which comprise the carbon-carbon triple bond ofsaid C₃-C₆alkynyl are not the point of attachment to the oxygen to whichR₂₅ is attached; R₂₆ and R₂₇ are each independently selected from thegroup consisting of H, C₁-C₆ alkyl, C₃-C₆ cycloalkyl, C₃-C₆ alkenyl,C₅-C₆ cycloalkenyl, and C₃-C₆ alkynyl provided the carbons whichcomprise the carbon-carbon double bond of said C₃-C₆ alkenyl, C₅-C₆cycloalkenyl, or the carbon-carbon triple bond of said C₃-C₆ alkynyl arenot the point of attachment to the nitrogen to which R₂₆ and R₂₇ areattached; R₇, R₈, R₉, R₁₀, R₁₁, R₁₂, R₁₃, and R₁₄ are each independentlyselected from the group consisting of H, C₁-C₆ alkyl, C₃-C₆ cycloalkyl,C₂-C₆ alkenyl, C₄-C₆ cycloalkenyl, C₂-C₆ alkynyl, CR₂₈R₂₉OR₃₀, C(O)R₃₁,CR₃₂(OR₃₃)OR₃₄, CR₃₅NR₃₆R₃₇, C(O)OR₃₈, C(O)NR₃₉R₄₀, CR₄₁R₄₂F, CR43F₂ andCF₃; R₂₈, R₂₉, R₃₀, R₃₁, R₃₂, R₃₅, R₄₁, R₄₂ and R₄₃ are eachindependently selected from the group consisting of H, C₁-C₆ alkyl,C₃-C₆ cycloalkyl, C₂-C₆ alkenyl, C₄-C₆ cycloalkenyl, C₂-C₆ alkynyl andC(O)R₄₄; R₃₃, R₃₄ and R₃₈ are each independently selected from the groupconsisting of H, C₁-C₆ alkyl, C₃-C₆ cycloalkyl, C₃-C₆ alkenyl, C₄-C₆cycloalkenyl, and C₃-C₆ alkynyl, provided the carbons which comprise thecarbon-carbon triple bond of said C₃-C₆ alkynyl are not the point ofattachment to the oxygen to which R₃₄ and R₃₈ are attached; R₃₆ and R₃₇are each independently selected from the group consisting of H, C₁-C₆alkyl, C₃-C₆ cycloalkyl, C₃-C₆ alkenyl, C₄-C₆ cycloalkenyl, and C₃-C₆alkynyl, provided the carbons which comprise the carbon-carbon triplebond of said C₃-C₆ alkynyl are not the point of attachment to thenitrogen to which R₃₆ and R₃₇ are attached; R₃₉ and R₄₀ are eachindependently selected from the group consisting of H, C₁-C₆ alkyl,C₃-C₆ cycloalkyl, C₂-C₆ alkenyl, C₄-C₆ cycloalkenyl, and C₃-C₆ alkynyl,provided the carbons which comprise the carbon-carbon triple bond ofsaid C₃-C₆ alkynyl are not the point of attachment to the nitrogen towhich R₃₉ and R₄₀ are attached; R₄₄ is selected from the groupconsisting of H, C₁-C₆ alkyl, C₃-C₆ cycloalkyl, C₂-C₆ alkenyl, C₄-C₆cycloalkenyl, and C₂-C₆ alkynyl; Ar is selected from the groupconsisting of

A₁, A₂, A₃, A₄, A₅, B₁, B₂, B₃, B₄, C₁, C₂, C₃, D₁, D₂, and D₃ are eachindependently selected from the group consisting of H, CN, halogen, NO₂,C₁-C₆ alkyl, C₃-C₆ cycloalkyl, C₂-C₆ alkenyl, C₄-C₆ cycloalkenyl, C₂-C₆alkynyl, OR₄₅, NR₄₆R₄₇, SR₄₈, N₃ and CH(—N═N—)—CF₃; R₄₅ is selected fromthe group consisting of H, C₁-C₆ alkyl, C₃-C₆ cycloalkyl, C₂-C₆ alkenyl,C₄-C₆ cycloalkenyl and C₃-C₆ alkynyl, provided the carbons whichcomprise the carbon-carbon triple bond of said C₃-C₆ alkynyl are not thepoint of attachment to the oxygen to which R₄₅ is attached; R₄₆ and R₄₇are each independently selected from the group consisting of H, C₁-C₆alkyl, C₃-C₆ cycloalkyl, C₃-C₆ alkenyl, C₅-C₆ cycloalkenyl, C₃-C₆alkynyl and C(O)R₅₀, provided the carbons which comprise thecarbon-carbon double bond of said C₅-C₆ alkenyl, C₄-C₆ cycloalkenyl, orthe carbon-carbon triple bond of said C₃-C₆ alkynyl are not the point ofattachment to the nitrogen to which R₄₆ and R₄₇ are attached; R₄₈ isselected from the group consisting of H, C₁-C₆ alkyl, C₃-C₆ cycloalkyl,C₂-C₆ alkenyl, C₄-C₆ cycloalkenyl, C₃-C₆ alkynyl and C(O)R₄₉, providedthe carbons which comprise the carbon-carbon triple bond of said C₃-C₆alkynyl are not the point of attachment to the sulfur to which R₄₈ isattached; R₄₉ is C₁-C₆ alkyl or C₃-C₆ cycloalkyl; R₅₀ is selected fromthe group consisting of H, C₁-C₆ alkyl, and C₃-C₆ cycloalkyl. R₇₅ isselected from the group consisting of H and CH₃; R₇₆ is selected fromthe group consisting of C₁-C₃ alkoxy and halogen; and X is halogen. 22.The method of claim 21, comprising the steps of: (a) converting acompound of formula 20(a):

to a compound of formula 21:

converting said compound of formula 21 to a compound of formula 21:

(b) converting said compound of formula 22 to a compound of formula 23:

(c) coupling said compound of formula 23 with a compound of formula 24:


23. The method of claim 22, comprising the steps of (a) reacting acompound of formula 20(a):

in the presence of a base, with

to form a compound of formula 21:

exposing said compound of formula 21 to H₂ (Pd/C), to form a compound offormula 22:

(b) reacting said compound of formula 22, in the presence of a Lewisacid, with

to form a compound of formula 23:

(c) reacting said compound of formula 23, in the presence of a base,with a compound of formula 24:


24. The method of claim 22, comprising the steps of: (a) converting acompound of formula 20(b):

to a compound of formula 22:

(b) converting said compound of formula 22 to a compound of formula 23:

(c) coupling said compound of formula 23 with a compound of formula 24:


25. The method of claim 24, comprising the steps of: (a) reacting acompound of formula 20(b):

to give a compound of formula 22:

(b) reacting said compound of formula 22, in the presence of a base,with

to form a compound of formula 23:

(c) reacting said compound of formula 23, in the presence of a base,with a compound of formula 24:


26. A compound according to formula 2: